Joel Kremer, MD; Zhan-Guo Li, MD, PhD; Stephen Hall, MD; Roy Fleischmann, MD; Mark Genovese, MD; Emilio Martin-Mola, MD, PhD; John D. Isaacs, PhD; David Gruben, PhD; Gene Wallenstein, PhD; Sriram Krishnaswami, PhD; Samuel H. Zwillich, MD; Tamas Koncz, MD; Richard Riese, MD, PhD; John Bradley, MD
Initial data from this study were reported at the 2011 European League Against Rheumatism, London, United Kingdom, 25–28 May 2011, and at the 2011 American College of Rheumatology meeting, Chicago, Illinois, 5–9 November 2011.
Acknowledgment: The authors thank the patients who were involved in this study, the ORAL Sync investigators, and the study team. The authors also thank the following study team members: Jill K. Lundberg, Tiffany Wolcott, Joanna Gibbs, Steve Ingham, Allison G. Brailey, and Kostia L. Franklin. For a list of the ORAL Sync investigators, see the Appendix.
Financial Support: By Pfizer. Editorial support was provided by Martin Goulding, PhD, at Complete Medical Communications and funded by Pfizer.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-3083.
Reproducible Research Statement: Study protocol: Available from Dr. Riese (e-mail, Richard.J.Riese@Pfizer.com). Statistical code and data set: Not available.
Corresponding Author: Richard Riese, MD, PhD, Pfizer Inc., 558 Eastern Point Road, Groton, CT 06340; e-mail, Richard.J.Riese@Pfizer.com.
Current Author Addresses: Dr. Kremer: Albany Medical College, The Center for Rheumatology, 1367 Washington Avenue, Suite 101, Albany, NY 12206.
Dr. Li: Peking University People's Hospital, Department of Rheumatology and Immunology, 42 North Lishi Road, Beijing, China 100044.
Dr. Hall: Cabrini Medical Centre, Isabella Street, Suite 43, Malvern, Victoria 3144, Australia.
Dr. Fleischmann: Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 810, Dallas, TX 75231.
Dr. Genovese: Stanford University, Division of Immunology and Rheumatology, 1000 Welch Roach, Suite 203, Stanford, CA 94304.
Dr. Martin-Mola: Hospital Universitario La Paz, Department of Rheumatology, 261 Paseo de la Castellana, Madrid 2804, Spain.
Dr. Isaacs: Newcastle University and Newcastle upon Tyne Hospitals NHS Trust, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne NE7 7DN, United Kingdom.
Drs. Gruben, Wallenstein, Krishnaswami, Zwillich, Riese, and Bradley: Pfizer Inc., 558 Eastern Point Road, Groton, CT 06340.
Dr. Koncz: Pfizer Inc., 235 East 42nd Street, New York, NY 10017.
Author Contributions: Conception and design: J. Kremer, R. Fleischmann, M. Genovese, J.D. Isaacs, D. Gruben, G. Wallenstein, S. Krishnaswami, S.H. Zwillich, T. Koncz, R. Riese.
Analysis and interpretation of the data: J. Kremer, Z.G. Li, R. Fleischmann, M. Genovese, E. Martin-Mola, D. Gruben, G. Wallenstein, S. Krishnaswami, S.H. Zwillich, T. Koncz, R. Riese, J. Bradley.
Drafting of the article: J. Kremer, R. Fleischmann, M. Genovese, E. Martin-Mola, J.D. Isaacs, G. Wallenstein, S. Krishnaswami, T. Koncz, R. Riese, J. Bradley.
Critical revision of the article for important intellectual content: J. Kremer, Z.G. Li, S. Hall, R. Fleischmann, M. Genovese, E. Martin-Mola, J.D. Isaacs, D. Gruben, G. Wallenstein, S. Krishnaswami, S.H. Zwillich, T. Koncz, R. Riese, J. Bradley.
Final approval of the article: J. Kremer, S. Hall, R. Fleischmann, M. Genovese, E. Martin-Mola, J.D. Isaacs, G. Wallenstein, S. Krishnaswami, S.H. Zwillich, T. Koncz, R. Riese, J. Bradley.
Provision of study materials or patients: Z.G. Li, R. Fleischmann, M. Genovese, J.D. Isaacs.
Statistical expertise: D. Gruben, G. Wallenstein.
Obtaining of funding: S.H. Zwillich.
Administrative, technical, or logistic support: G. Wallenstein, J. Bradley.
Collection and assembly of data: J. Kremer, S. Hall, R. Fleischmann, M. Genovese, J.D. Isaacs, D. Gruben, G. Wallenstein, S. Krishnaswami, R. Riese, J. Bradley.
Kremer J, Li Z, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: A Randomized Trial. Ann Intern Med. 2013;159:253-261. doi: 10.7326/0003-4819-159-4-201308200-00006
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Published: Ann Intern Med. 2013;159(4):253-261.
Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA.
To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.
1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).
114 centers in 19 countries.
792 patients with active RA despite nonbiologic DMARD therapy.
Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily.
Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)–defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments.
Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups.
Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.
Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.
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